1. Field of the Invention
The present invention provides pharmaceutically active ornithine compounds, particularly to pharmaceutically acceptable ammonium salts of Nδ-acyl derivatives of Nα(4-amino-4-deoxypteroyl)-L-ornithine compounds. Preferred ammonium salts of the invention have superior chemical stability than corresponding free acid formulations.
2. Background
Nα-(4-amino-4-deoxypteroyl)-L-ornithine (“APA-L-Orn”) has a structure according to Formula I: in which R is hydrogen. It has been reported to be a potent inhibitor of dihydrofolate reductase (DHFR) and of folylpolyglutamate synthetase (FPGS), but to be relatively inactive as an inhibitor of cell growth in culture, and it has been suggested that amino-substituted prodrug derivatives of it would be of interest because of possible increased cellular uptake. Rosowsky et al., J. Med. Chem., Vol. 29, pp 655-660 (1986).
A series of acidic compounds according to formula I were disclosed in U.S. Pat. No. 4,767,761 in which R is a benzoate derivative, e.g., —CO—Ar—COOR1 where Ar is an aromatic group and R1 is hydrogen or lower alkyl having I to 5 carbon atoms. Such compounds are hereinafter referred to as acidic compounds of Formula Ia.
The acidic compounds of Formula Ia disclosed in '761 exhibit remarkably high inhibitory activity against the growth of tumor cells resistant to methotrexate, such as the human cell lines SCC 15/R1 and SCC 25/R1. The inhibitory activity of acidic compounds of Formula Ia was unexpectedly higher than inhibitory activity for other Nδ-acyl derivatives of APA-L-Orn. Acidic compounds according to Formula Ia are subject to gradual decomposition when stored in a dry state as a powder or when stored in an alkaline solution having a pH of greater than about 7.5, or more typically a pH of between about 7.5 and 9. Further, acidic compounds according to Formula Ia are not soluble in aqueous solutions without the addition of a basic additive.
It would be desirable to have new formulations of compounds according to Formula Ia which have good shelf-life in dry formulations and are readily soluble in water without the addition of basic additives. Particularly desirable would be pharmaceutically acceptable salts of compounds of Formula Ia which exhibit high inhibitory activity against the growth of methotrexate-resistant cells and which have increased stability as compared to the corresponding acidic compound of Formula Ia.